[P1.85]: Variant Rett syndrome in a girl with a pericentric X‐chromosome inversion leading to overexpression of the MECP2 gene

The ventral midbrain contains a diverse array of neurons, including dopaminergic (DA), red nucleus (RN) and motorneurons. DA neurons are further organized into several anatomically and functionally distinct subclasses, including the substantia nigra (SN) and the ventral tegmental area (VTA). DA and RN neurons have been shown to arise from a Sonic Hedgehog (Shh)-expressing precursor population in the ventral mesencephalon. However, Shh expression appears dynamic and could define different ventral progenitor domains at distinct developmental points. Some progenitors that express Shh, also initially express the Hedgehog target gene Gli1, but later Gli1 is expressed only in precursors lateral to the Shh-expressing domain. Using genetic inducible fate mapping, we investigated whether the medial–lateral position of progenitors, which is defined by the time when the cells express Gli1 or Shh, determines distinct ventral midbrain cell types. Indeed, precursors in the most medial ventral mesencephalon, which eventually downregulate Shh expression, give rise to DA neurons of the SN and lateral VTA. In contrast, adjacent progenitors that maintain Shh expression, have a different potential and primarily give rise to the medial and lateral VTA. Both populations also give rise to RN neurons. We further show that midbrain motorneurons are derived from lateral progenitors that are Gli1-positive but Shh-negative. Moreover, we demonstrate that ventral midbrain astrocytes are derived from Shhand Gli1-expressing progenitors. We thus define a ventral midbrain precursor map based on progenitor position and Gli1/Shh expression and provide evidence that the diversity of midbrain DA neurons is at least partially determined by the mediallateral position of their progenitors in the ventral mesencephalon. We are now investigating whether Shh signaling has a functional role in the specification of DA subtypes.